Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes
An elevated level of circulating homocysteine (Hcy) has been regarded as an independent risk factor for cardiovascular disease; however, the clinical benefit of Hcy lowering-therapy is not satisfying. To explore potential unrevealed mechanisms, we investigated the roles of Ca<sup>2+</sup>...
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MDPI AG
2023-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/6/952 |
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| author | Gui-Lan Chen Bo Zeng Hongni Jiang Nikoleta Daskoulidou Rahul Saurabh Rumbidzai J. Chitando Shang-Zhong Xu |
| author_facet | Gui-Lan Chen Bo Zeng Hongni Jiang Nikoleta Daskoulidou Rahul Saurabh Rumbidzai J. Chitando Shang-Zhong Xu |
| author_sort | Gui-Lan Chen |
| collection | DOAJ |
| description | An elevated level of circulating homocysteine (Hcy) has been regarded as an independent risk factor for cardiovascular disease; however, the clinical benefit of Hcy lowering-therapy is not satisfying. To explore potential unrevealed mechanisms, we investigated the roles of Ca<sup>2+</sup> influx through TRPC channels and regulation by Hcy–copper complexes. Using primary cultured human aortic endothelial cells and HEK-293 T-REx cells with inducible TRPC gene expression, we found that Hcy increased the Ca<sup>2+</sup> influx in vascular endothelial cells through the activation of TRPC4 and TRPC5. The activity of TRPC4 and TRPC5 was regulated by extracellular divalent copper (Cu<sup>2+</sup>) and Hcy. Hcy prevented channel activation by divalent copper, but monovalent copper (Cu<sup>+</sup>) had no effect on the TRPC channels. The glutamic acids (E542/E543) and the cysteine residue (C554) in the extracellular pore region of the TRPC4 channel mediated the effect of Hcy–copper complexes. The interaction of Hcy–copper significantly regulated endothelial proliferation, migration, and angiogenesis. Our results suggest that Hcy–copper complexes function as a new pair of endogenous regulators for TRPC channel activity. This finding gives a new understanding of the pathogenesis of hyperhomocysteinemia and may explain the unsatisfying clinical outcome of Hcy-lowering therapy and the potential benefit of copper-chelating therapy. |
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| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T02:42:00Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-9fa36fe44b604655887cc5a0beb4faf42023-11-18T09:31:07ZengMDPI AGBiomolecules2218-273X2023-06-0113695210.3390/biom13060952Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper ComplexesGui-Lan Chen0Bo Zeng1Hongni Jiang2Nikoleta Daskoulidou3Rahul Saurabh4Rumbidzai J. Chitando5Shang-Zhong Xu6Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKCentre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UKAn elevated level of circulating homocysteine (Hcy) has been regarded as an independent risk factor for cardiovascular disease; however, the clinical benefit of Hcy lowering-therapy is not satisfying. To explore potential unrevealed mechanisms, we investigated the roles of Ca<sup>2+</sup> influx through TRPC channels and regulation by Hcy–copper complexes. Using primary cultured human aortic endothelial cells and HEK-293 T-REx cells with inducible TRPC gene expression, we found that Hcy increased the Ca<sup>2+</sup> influx in vascular endothelial cells through the activation of TRPC4 and TRPC5. The activity of TRPC4 and TRPC5 was regulated by extracellular divalent copper (Cu<sup>2+</sup>) and Hcy. Hcy prevented channel activation by divalent copper, but monovalent copper (Cu<sup>+</sup>) had no effect on the TRPC channels. The glutamic acids (E542/E543) and the cysteine residue (C554) in the extracellular pore region of the TRPC4 channel mediated the effect of Hcy–copper complexes. The interaction of Hcy–copper significantly regulated endothelial proliferation, migration, and angiogenesis. Our results suggest that Hcy–copper complexes function as a new pair of endogenous regulators for TRPC channel activity. This finding gives a new understanding of the pathogenesis of hyperhomocysteinemia and may explain the unsatisfying clinical outcome of Hcy-lowering therapy and the potential benefit of copper-chelating therapy.https://www.mdpi.com/2218-273X/13/6/952homocysteinecalcium channelTRPCTRPM2copperendothelial cells |
| spellingShingle | Gui-Lan Chen Bo Zeng Hongni Jiang Nikoleta Daskoulidou Rahul Saurabh Rumbidzai J. Chitando Shang-Zhong Xu Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes Biomolecules homocysteine calcium channel TRPC TRPM2 copper endothelial cells |
| title | Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes |
| title_full | Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes |
| title_fullStr | Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes |
| title_full_unstemmed | Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes |
| title_short | Ca<sup>2+</sup> Influx through TRPC Channels Is Regulated by Homocysteine–Copper Complexes |
| title_sort | ca sup 2 sup influx through trpc channels is regulated by homocysteine copper complexes |
| topic | homocysteine calcium channel TRPC TRPM2 copper endothelial cells |
| url | https://www.mdpi.com/2218-273X/13/6/952 |
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